Phenylbutyrate, an aromatic fatty acid, can be purified from a biological sample (e.g., mammalian urine or plasma) or chemically synthesized. Sodium phenylbutyrate has been approved by the U.S. Food and Drug Administration as an orphan drug for treating hyperammonemia (Samid et al. (1992) Cancer Res. 52: 1988-1992). It has also been clinically used in patients with in-born genetic errors which lead to liver failure or urea cycle disorders.
Radiation fibrosis, a local defect, is a frequent sequela of therapeutic or accidental radiation overexposure of normal tissues. It results from a complex tissue repair response whose predominant characteristics are massive deposition of extracellular matrix and excessive fibroblast proliferation. An ulcer is also a local defect, i.e., excavation of the surface of an organ or tissue. There is a need for effective treatment of both disorders.
The present invention is based on the unexpected discovery that certain aromatic fatty acids can be used to effectively treat an ulcer and radiation fibrosis.
Thus, this invention features a method for treating a subject having an ulcer or radiation fibrosis. The method includes topically administrating to the subject an effective amount of a compound and a pharmaceutically acceptable carrier. The compound, which can be synthesized by well-known methods or purchased from commercial suppliers, has the following formula: 
R1 and R2, independently, is H or C1xcx9cC6 alkyl; R3 is aryl or heteroaryl; and n is 0, 1, 2, 3, 4, 5, or 6. A subset of the compounds encompassed by the above formula are featured by that R3 is phenyl, n is 0, 1, or 2, and each of R1 and R2, independently, is H, methyl, or ethyl. Three exemplary compounds are 2-phenylbutyrate, 3-phenylbutyrate, and 4-phenylbutyrate.
Alkyl, aryl, and heteroaryl mentioned above include both substituted and unsubstituted moieties. The term xe2x80x9csubstitutedxe2x80x9d refers to one or more substituents (which may be the same or different), each in replace of a hydrogen atom. Examples of substituents include, but are not limited to, halogen, amino, hydroxyl, mercapto, cyano, C1xcx9cC6 alkyl, C1xcx9cC6 alkenyl, C1xcx9cC6 alkoxy, aryl, heteroaryl, or heterocyclyl, wherein alkyl, alkenyl, alkoxy, aryl, heteroaryl, and heterocyclyl are optionally substituted with C1xcx9cC6 alkyl, halogen, amino, hydroxyl, mercapto, cyano. The term xe2x80x9carylxe2x80x9d refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and pyrenyl. The term xe2x80x9cheteroarylxe2x80x9d refers to a hydrocarbon ring system having at least one aromatic ring which contains at least one heteroatom such as O, N, or S. Examples of heteroaryl moieties include, but are not limited to, pyridinyl, carbozolyl, and indolyl.
The term xe2x80x9caromatic fatty acidsxe2x80x9d used herein refers to all the compounds covered by the above formula, and includes the compounds themselves, as well as their salts and their prodrugs, if applicable. Such salts, for example, can be formed between a negatively charged substituent (e.g., carboxylate) on an aromatic fatty acid compound and a cation. Suitable cations include, but are not limited to, sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as teteramethylammonium ion. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing the aromatic fatty acids described above. As used herein, the term xe2x80x9ctreatmentxe2x80x9d refers to administration of a topical composition to a subject with the purpose to cure, heal, alleviate, relieve, remedy, ameliorate, improve or prevent an ulcer or radiation fibrosis, its symptoms or the predisposition toward it.
Also within the scope of this invention is the use of the above-described compounds for the manufacture of a medicament for the treatment of an ulcer or radiation fibrosis.
Other features or advantages of the present invention will be apparent from the following detailed description of several embodiments, and also from the appending claims.
One aspect of this invention is a method for treating a subject having an ulcer or radiation fibrosis by using a topical composition that contains an effective amount of one or more aromatic fatty acids described above and a pharmaceutically acceptable carrier.
An effective amount of an aromatic fatty acid is the amount of the compound which, upon administration to a subject in need of treatment or prophylaxis of an ulcer or radiation fibrosis, is required to confer therapeutic effect on the treated subject. It may range from 0.1% to 40% (e.g., 0.1% to 10%) by weight of a topical composition. As recognized by those skilled in the art, the effective doses vary depending on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as the use of other anti-ulcer or anti-radiation fibrosis agents. Effective amounts and treatment regimens for any particular subject (e.g., human, dog, or cat) will also depend upon a variety of other factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, the severity and course of the disease, and the patient""s disposition to the disease.
A pharmaceutically acceptable carrier may include water, a solvent, an emollient, a surfactant, a preservative, or a combination thereof. Water, when present, can be in an amount of 5 to 95% by weight. Other than water, the biological acceptable carrier can also contain a relatively volatile solvent such as a monohydric C1-C3 alkanol (e.g., methyl alcohol or ethyl alcohol) in an amount of 1 to 70% by weight, and an emollient such as those in the form of silicone oils and synthetic esters in an amount of 0.1 to 30% by weight. Anionic, nonionic, or cationic surfactants may also be included in the biological acceptable carrier. The concentration of total surfactants may be from 0.1 to 40% by weight. Examples of anionic surfactants include soap, alkyl ether sulfate and sulfonate, alkyl sulfate and sulfonate, alkylbenzene sulfonate, alkyl and dialkyl sulfosuccinate, C1-C2, acyl isethionate, acyl glutamate, C8-C20 alkyl ether phosphate, and a combination thereof Examples of nonionic surfactants include C10-C20 fatty alcohol or acid hydrophobe condensed with from 2 to 100 moles of ethylene oxide or propylene oxide per mole of hydrophobe; C2 to C10 alkyl phenol condensed with from 2 to 20 moles of alkylene oxide; mono and di- fatty acid ester of ethylene glycol; fatty acid monoglyceride; sobitan, mono- and di-C8 to C20 fatty acid; block co-polymer (ethylene oxide/propylene oxide); polyoxyethylene sorbitan, and a combination thereof. Preservatives may also be included in the biological acceptable carrier to prevent growth of potentially harmful microorganisms, and may be employed in an amount of 0.01 to 2% by weight. Examples of preservatives include alkyl ester of para-hydroxybenzoic acid, hydantoin derivative, propionate salt, and a variety of quaternary ammonium compounds. Each preservative should be selected based on its compatibility with other ingredients in the topical composition.
A topical composition for practicing this invention may be provided as an aqueous, anhydrous or emulsion-like formulation, such as oil, cream, spray (aerosol or non-aerosol), gel (oral or non-oral), or ointment. When an anhydrous formulation is desired, various forms may be adopted, e.g., sticks, roll-ons, adhesive patches, or overnight masks. Peelable masks can be formulated by placing the composition as a gel or paste on a protective layer made of a film-forming polymer (e.g., polyvinyl alcohol) and an adhesive promoting polymer (e.g., hydrophobic acrylate or methacrylate polymer, such as Pemulen TR2.RTM. from the B. F. Goodrich Company).
An example of such a topical composition used for treating an ulcer or radiation fibrosis is an ointment. An ointment composition can be formulated with an aromatic fatty acid suspended or dissolved in a carrier, such as mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, water, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetyl alcohol, 2-octyldodecanol, and stearyl alcohol. The topical composition can also be a sustained release formulation (e.g., a patch) for delivering an aromatic fatty acid over an extended period of time. Another example of the topical composition is oral gel, which can be particularly used in the oral mucosa. The oral gel can include a viscose-enhancing agent (such as sodium polyacrylate) and an aromatic fatty acid ranging from 0.1% to 10% by weight. A further example of the topical composition is a liposomal composition in which an aromatic fatty acid is encapsulated in liposomes. As well known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposome compositions are formed by mono-or multilamellar hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, pharmaceutically acceptable, and metabolizable lipid capable of forming liposomes can be used. A composition in liposome form can contain, in addition to an aromatic fatty acid, stabilizers, excipients, and preservatives. Examples of lipid substances include, but are not limited to, cholesterol, phospholipids, and phosphatidylcholines. Methods for forming liposomes are known in the art as described, for example, in Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), pp. 33.
Other than topical administration, a pharmaceutical composition containing an aromatic fatty acid may be administered with a pharmaceutically acceptable carrier to a subject orally, parenteraIly, sublingually, rectally, enterally, or by pulmonary absorption. The pharmaceutical composition can be used for treating an ulcer or radiation fibrosis. Examples of parenteral dosage forms include aqueous solutions, isotonic saline or 5% glucose of the active agent, or other well-known pharmaceutically acceptable excipient. Solubilizing agents such as cyclodextrans or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the aromatic fatty acids. The pharmaceutical composition can be formulated into dosage forms, such as a capsule, a gel seal, or a tablet for oral administration, or other types of formulations for other routes of administration. Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets, on the other hand, may be formulated in accordance with conventional procedures by compressing mixtures of an aromatic fatty acid with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite.